2.2 Dichloro -1,1,-difluoroethyl-1,2,2,2- tetrofluoroethyl ether as an inhalation anesthetic

ABSTRACT

This disclosure is directed to novel ethers of the formula:

This is a division of application Ser. No. 170,954, filed Aug. 11, 1971,now U.S. Pat. No. 3,764,706.

This invention relates to the novel ethers of the formula:

    CF.sub.3 CH.sub.a X.sub.b --O--CF.sub.2 CH.sub.c F.sub.d Cl.sub.e

wherein X is fluorine, chlorine or bromine, preferably fluorine, a is 1or 2, b is 0 or 1, a plus b are 2, preferably both a and b being 1, c is0 or 1, d is 0, 1 or 2, e is 0, 1 or 2, c plus d plus e are 3,preferably each of c, d, and e is 1, and a plus c are 1 or 2, preferably2, with the proviso that when e is 1 or 2, X, if present, is fluorine orbromine, preferably fluorine. Preferably when e is 1 or 2, b is 1. Theseethers which have less than 8 fluorine atoms per molecule, especially 6or 7 fluorine atoms per molecule, can be used to produce anesthesia inanesthetic-susceptible mammals. All of the ethers of this invention areeasily miscible with other organic liquids, including fats and oils, andhave useful solvent properties. These ethers are useful, for example, assolvents for fluorinated olefins and other fluorinated materials such asfluorowaxes. The ethers can also be used to prepare pastes anddispersions of such fluorine-containing materials useful for coatingsand the like, and can be used as degreasing agents. In the lattercapacity, for example, the ether compounds of this invention can be usedas solvents to remove grease or other oily substances from metalsurfaces that are to be painted.

A highly preferred compound of the invention is 1,2,2,2-tetrafluoroethyl1',1',2'-trifluoro-2'-chloroethyl ether having the formula CF₃CHF--O--CF₂ CHFCl. This compound is normally a clear, colorless liquidwith an ethereal odor. This ether has the following physical properties:b.p. 65.5°C. at 760 mm.; vapor pressure 175 mm. at 25°C.; specificgravity 1.52; and molecular weight 234.5. The compound is nonflammable,soda lime stable, and a potent anesthetic for inhalationanesthetic-susceptible mammals.

The compounds of the present invention can be prepared by thefluorination, chlorination or bromination of the correspondinghalogen-containing ethers to substitute one or two additional halogenatoms per molecule in place of hydrogen atoms of the feed. The ethers ofthe invention may also be formed by the replacement of a halogen atom onthe feed by another halogen atom, e.g., the substitution of a fluorineatom for a bromine atom. Suitable feedstocks for these reactions can beobtained in several ways and one procedure involves the reaction of aperhalogenated ethylene with 2,2,2-trifluoroethanol. The perhalogenatedethylenes have the formula CF₂ =CX₂ in which X is fluorine or chlorine.These reactions can be conducted in the presence of potassium hydroxideand a small amount of α-pinene. Suitable temperatures for the reactionsare generally in the range of about 30° to 50°C.

The chlorination or bromination of the ethers resulting from theforegoing reaction can be conducted with the use of molecular chlorineor bromine. Chlorine can be reacted conveniently at temperatures ofabout 50° to 60°C. in the presence of light. In the reaction gaseouschlorine can be passed into the liquid ether feed, and the chlorine canbe added to the reactor at the approximate rate it reacts. If desirable,the reactor can be cooled to control the reaction temperature.Bromination of the ethers can be effected by passing a mixture ofgaseous bromine and an inert gas such as nitrogen along with ether feedin the vapor phase through a reaction zone maintained at elevatedtemperatures, e.g. about 400° to 550°C. In either of these reactionsystems the products can be separated by fractional distillation or gaschromatography techniques.

The ethers of this invention can be made by a fluorination processinvolving the use of molecular fluorine. For example CF₃ CH₂ OCF₂ CHFClcan then be converted to a mixture containing CF₃ CHFOCF₂ CHFCl, CF₃ CH₂OCF₂ CF₂ Cl and CF₃ CHFOCF₂ CF₂ Cl, all compounds of the presentinventions, by reaction with gaseous fluorine to replace one of thehydrogen atoms on the 1-carbon atom which bears two hydrogen atomsand/or replace the hydrogen atom on the 2-carbon atom bearing a chlorineatom. The fluorination can be accomplished by mixing the feed compoundwith carbon tetrachloride or other fluorine and/or chlorine-containingalkane solvents which are preferably perhalogenated, and then contactingthe mixture with gaseous fluorine at reduced temperatures, e.g. belowabout 0°C., preferably about -20° to 0°C. Lower alkyl ethers which areperhalogenated with one or both of chlorine or fluorine may also besuitable solvents. Hydrogen fluorine is evolved from the reactionmixture during this fluorination procedure and the Hf can be collectedby passage of the evolved gases through a water scrubber. After asubstantial amount of the feed ether has reacted, the desired productscan be separated from the reaction mixture by gas chromatography. Thisfluorination procedure can be used to prepare various compounds of theinvention from the corresponding ethers.

The following examples will serve further to illustrate the presentinvention.

EXAMPLE I Preparation of the Intermediate CF₃ CH₂ OCF₂ CHF₂

Tetrafluoroethylene (400 g.) was added as a gas at 300-500 psi to astirred one liter autoclave containing a solution of potassium hydroxide(50 g.) in CF₃ CH₂ O (400 cc.) and also a small amount of α-pinene (10g.). The autoclave was heated to 40°C. to initiate the reaction. Thereaction then proceeded smoothly with a slight exotherm and wasmaintained at 35°-45°C. The crude product was washed with water and thenfractionally distilled to obtain 350 g. of CF₃ CH₂ OCF₂ CHF₂, b.p.55.5°C. at 760 mm.

EXAMPLE II Preparation of CF₃ CHClOCF₂ CF₂ H

CF₃ CH₂ OCF₂ CF₂ H (140 g.) was reacted with chlorine gas at atemperature of 50°-60°C. in a glass apparatus in the presence ofincandescent light. When 0.7 mole of chlorine per mole of ether hadreacted, the crude product weighed 157 g. and contained 60%, of CF₃CHClOCF₂ CF₂ H as shown by gas chromatography. This product wasseparated and purified by fractional distillation and preparative vaporphase chromatography. The product analyzed as follows:

Calculated for C₄ H₂ ClF₇ O: C, 20.5; H, 0185, b.p. 66°C. Found: C,20.8; H, 1.03.

    Specific gravity   1.5                                                        Vapor pressure     175 mm. Hg./25°C.                                   Odor               slight                                                     Flammability       non-flammable                                          

The structure CF₃ CHClOCF₂ CF₂ H was confirmed by the n.m.r. andinfrared spectra.

EXAMPLE III Preparation of CF₃ CHBrOCF₂ CF₂ H

CF₃ CH₂ OCF₂ CF₂ H (110 g.) was reacted with bromine (125 g.) by passinga mixture of the two diluted with a stream of nitrogen through a 12 inch× 1 inch glass tube heated to 475°C. The effluent product was condensedin a "Dry Ice" trap and purified by fractional distillation andpreparative gas chromatography to give CF₃ CHBrOCF₂ CF₂ H., b.p. 80°C.,n_(D) ²⁵ 1.3155. This product analyzed as follows:

Calculated for C₄ H₂ F₇ BrO: C, 17.4; H, 0.74. Found: C, 17.52; H, 0.73.

    Specific gravity   1.8                                                        Vapor pressure     100 mm. Hg./25°C.                                   Odor               not unpleasant                                             Flammability       non-flammable                                          

EXAMPLE IV Preparation of CF₃ CHFOCF₂ CF₂ H

CF₃ CH₂ OCF₂ CF₂ H (100 g.) was fluorinated at -20°C. in CCl₄ (350 cc.)in a glass reactor using fluorine diluted with argon (F₂ at 80 cc./min.argon at 160 cc./min.). After seven hours, conversion of the feed etherto CF₃ CHFOCF₂ CHF₂ was 28 mole %. The product CF₃ CHFOCF₂ CHF₂ wasisolated by distillation and preparative gas chromatography, b.p. 41°C.,and analyzed as follows:

Calculated for C₄ H₂ F₈ O: C, 22.0; H, 0.92. Found: C, 22.1; H, 0.9.

    Specific gravity   1.4                                                        Vapor pressure     430 mm. Hg./25°C.                                   Odor               None                                                       Flammability       non-flammable                                          

The assigned structure was confirmed by the n.m.r. spectrum.

EXAMPLE V Preparation of CF₃ CHFOCF₂ CHCl₂ and CF₃ CHFOCF₂ CFCl₂

CF₃ CH₂ OCF₂ CHCl₂ (232 g.) (proposed as in Example I but using CF₂ =CCl₂ instead of CF₂ = CF₂) was fluorinated in Freon 113 (CCl₃ CF₃) (850cc.) at -20°C. in a glass reactor using fluorine diluted with argon, (F₂at 80 cc./min., argon at 160 cc./min.). After seven hours, 42% of thestarting ether was converted to a mixture of CF₃ CHFOCF₂ CHCl₂ and CF₃CH₂ OCF₂ -- CFCl₂. CF₃ CHFOCF₂ CHCl₂, b.p. 89°C., n_(D) ²⁰ 1.3261, wasisolated by gas chromatography and analyzed as follows:

Calculated for C₄ H₂ Cl₂ F₆ O: C, 19.19; H, 0.8. Found: C, 19.2; H,0.88.

    Specific gravity   1.54                                                       Vapor pressure     58 mm. Hg./25°C.                                    Odor               ethereal                                                   Flammability       Non-flammable                                          

The resulting mixture of fluorinated ethers can be further fluorinatedusing the same conditions to give additional quantities of CF₃ CHFOCF₂CFCl₂, b.p. 75°C., which can be separated by gas chromatography. Thisproduct analyzed as follows:

Calculated for C₄ HCl₂ F₇ O: C, 17.85; H, 0.37. Found: C, 18.10; H,0.40.

    Specific gravity   1.67                                                       Vapor pressure     120 mm. Hg./25°C.                                   Flammability       non-flammable.                                         

EXAMPLE VI

2,2,2-Trifluoroethyl 1',1',2'-trifluoro-2'-chloroethyl ether (CF₃ CH₂OCF₂ CHFCl) (216.5 g., 1.0 m.) (prepared as in Example I but using CF₂ =CFCl instead of CF₂ = CF₂) in 900 ml. of carbon tetrachloride wasfluorinated at -15°C. in a glass flask using 33% fluorine in argon (F₂at 80 cc./min., argon at 160 cc./min.) at a rate of 0.2 mole fluorineper hour. After seven hours, 36% of the starting ether had beenconverted to fluorinated products, and the reaction mixture analyzed asfollows:

0.9% CF₃ CHF-- O--CF₂ CF₂ Cl

2.35% CF₃ CH₂ --O--CF₂ CF₂ Cl

2.59% CF₃ CHF--O--CF₂ CHFCl

5.56% CF₃ CH₂ --O--CF₂ CHFCl

88.53% CCl₄

The products CF₃ CHF--O--CF₂ CHFCl, CF₃ CH₂ OCF₂ CF₂ Cl, and CF₃ CHFOCF₂--CF₂ Cl were separated from unreacted starting ether and were recoveredby fractional distillation. These ether products were further purifiedby preparative gas chromatography. The preparative gas chromatographyproducts separated were as follows:

CF₃ CHFOCF₂ CHFCl, b.p. 65.5°C. Calculated for C₄ H₂ ClF₇ O: F, 56.6%.Found: F, 56.6%.

    Specific gravity   1.52                                                       Vapor pressure     175 mm. Hg./25°C.                                   Odor               ethereal                                                   Flammability       non-flammable                                          

CF₃ CH₂ OCF₂ CF₂ Cl, b.p. 57°C. Calculated for C₄ H₂ ClF₇ O: F, 56.6%.Found: F, 56.7%.

    Specific gravity   1.48                                                       Vapor pressure     240 mm. Hg./25°C.                                   Odor               ethereal                                                   Flammability       non-flammable                                          

CF₃ CHFOCF₂ CF₂ Cl, b.p. 42.5°C. Calculated for C₄ HClF₈ O: F, 60.1%.Found: F, 60.1%.

    Specific gravity   1.52                                                       Vapor pressure     410 mm. Hg./25°C.                                   Flammability       non-flammable.                                         

The identity of each of these ether products was confirmed by thenuclear magnetic resonance (n.m.r.) spectrum.

EXAMPLE VII Preparation of CF₃ CHBrOCF₂ CHFCl

CF₃ CH₂ OCF₂ CHFCl (104 g.) and bromine (85 g.) were vaporized in astream of nitrogen at 15-20 l/hr. The gaseous mixture was then passedthrough a 1 inch × 12 inch glass tube at 475°C. The crude product (137g.) was condensed in a "Dry Ice" trap and purified by fractionaldistillation and preparative gas chromatography. The product CF₃CHBrOCF₂ CHFCl had b.p. 109° C., n_(D) ²⁰ 1.3525 and analyzed asfollows:

Calculated for C₄ H₂ BrClF₆ O: C, 16.25; H, 0.68. Found: C, 16.34; H,0.57.

    Specific gravity   1.9                                                        Vapor pressure     30 mm. Hg./25°C.                                    Odor               not unpleasant                                             Flammability       non-flammable                                          

The structure of the product ether was confirmed by the n.m.r. andinfrared spectra.

In order to determine the potency of the ethers of the present inventionas inhalation anesthetics in combination with oxygen, tests were carriedout on mice. The compounds tested were at least 99.5% pure as determinedby vapor phase chromatography. In the tests, the ether compound isadministered to test mice by a standard procedure in which a measuredquantity of the agent is placed in a laboratory jar and allowed tocompletely vaporize so as to give a calculated vapor concentration. Thetest mice are then quickly placed in the jar and observed. Anesthesia isdetermined by observing the righting reflex of the mice. Recovery timeis measured beginning when the mice are transferred from the test jar toroom air and ending when the mice are observed to be able to walk.

In such tests the 1,2,2,2-tetrafluoroethyl1',1',2'-trifluoro-2'-chloroethyl ether induced a light level ofanesthesia in 53 seconds when used at a vapor concentraiton of 2%. Theinduction was accompanied by brief excitement. Recovery required 75seconds. At 2.5% concentration the induction period lasted 40 secondsand recovery required 52 seconds. There was brief excitement duringinduction and recovery. Respiration slowed to 64 per minute duringmaintenance of the anesthesia, but the color of the mice remained good.

Thus it is seen that the compound 1,2,2,2-tetrafluoroethyl1',1',2'-trifluoro-2'-chloroethyl ether exhibited good anestheticproperties in inhalation anesthetic-susceptible mammals, giving rapidinduction and recovery and moderate respiratory depression. The compoundis soda lime stable, and lends itself well to effective use as aninhalant anesthetic in respirable mixtures containing life-supportingconcentrations of oxygen.

Using a 2.5% vapor concentration of 2-chloroperfluoroethyl2',2',2'-trifluoroethyl ether a low level of anesthesia was induced withhyperexcitability in 7 minutes. One of five mice died of respiratoryfailure during maintenance of the anesthesia. The animals were excitablein recovery and one became cyanotic, but survived.

Using a 1.25% vapor concentration of 2-hydroperfluoroethyl1'-chloro-2'-2'-2'-trifluoroethyl ether, very light anesthesia wasinduced in the mice in 4.7 minutes. Respiration was slowed and animalsrose to their feet when stimulated. At 2.5% concentration there was deepanesthesia in 1.3 minutes; recovery required 1.9 minutes. Respirationswere abdominal during maintenance of the anesthesia, and the animalswere hyperflexic and twitching during recovery. At 5% concentration theinduction required 0.5 minute and the recovery took 3.9 minutes. Theanesthesia was very deep at this concentration, one mouse in fivearching its back during maintenance, and two in five arching theirsduring recovery. There was jumping and twitching, and respiration wasvery depressed. Recovery was accompanied by marked tremors.

The compound 1-bromo-1-hydroperfluoroethyl 2'-hydroperfluoroethyl etherwhen used at 1.0 % vapor concentration induced anesthesia in 1 minute 14seconds; recovery therefrom required 3 minutes 12 seconds. Maintenanceat this concentration was marked by motor activity at the start, leadingto flaccidity and much respiratory depression. At 1.5% vaporconcentration anesthesia was induced in 1 minute 8 seconds and recoveryrequired 4 minutes 2 seconds. Induction was accompanied by muchexcitement. Maintenance proceeded as with 1% concentration, with therespiration rate being depressed to 20 per minute. At 2.5% vaporconcentration there was marked excitement on induction, which required43 seconds, and the respiration rate fell to 16 per minute. Recoverytook 6 minutes 37 seconds.

Using 1-bromo-2,2,2-trifluoroethyl 2'-chloro-1',1',2'-trifluoroethylether at 0.25% vapor concentration required 2 minutes 32 seconds toinduce a light anesthesia with moderate respiratory depression duringmaintenance. Recovery took 6 minutes 13 seconds. At 0.5% concentrationthe induction occurred in 2 minutes 35 seconds and the recovery in 4minutes 58 seconds. The excitement phase during induction was long, andmoderate respiratory depression was observed during maintenance. At0.75% concentration the inducement required 1 minute 16 seconds; againit was with excitement. The respiration rate fell to 40-60 per minuteduring maintenance. Recovery took 9 minutes. A level of 2.5% vaporconcentration was lethal to all of the test mice.

Using 0.5% vapor concentration of 2,2-dichloro-1,1-difluoroethyl1',1',2',2'-tetrafluoroethyl ether, induction of a very light anesthesiarequired 1 minute 29 seconds and recovery therefrom took 52 seconds. Theinduction was accompanied by mild excitement. At a level of 1.0% a lightanesthesia was induced, again with mild excitement, in 35 seconds.Respiration was jerky and gasping during maintenance. Recovery required3 minutes 24 seconds. Smooth induction occurred in 10 seconds when using2.5% vapor concentration. There was some respiratory depression duringmaintenance and mild cyanosis in recovery. The recovery took 9 minutesand the mice were sluggish afterwards.

At a vapor concentration of 5%, the compound 1,2,2,2-tetrafluoroethyl1',1',2'-trifluoro-2',2'-dichloroethyl ether induced anesthesia in thetest mice in 1 minute 30 seconds. The animals were restless inmaintenance, with gasping, jumping, urination, and some cyanosis. Therecovery was with excitement and required 35 seconds.

The compounds 2-chloro-1,1,2,2-tetrafluoroethyl1',2',2',2'-tetrafluoroethyl ether and 1,2'-dihydroperfluorodiethylether were both tested at 2.5% and 5.0% vapor concentrations and wereobserved to have a sedative effect on the mice; but they did not induceanesthesia.

Examples of other halogenated diethyl ethers which I have considered aspossible anesthetics are listed below, but none was satisfactory.

    ______________________________________                                        Compound       Properties                                                     ______________________________________                                        CF.sub.3 CH.sub.2 -O-CF.sub.2 CHFCl                                                          Convulsant                                                     CF.sub.3 CH.sub.2 -O-CF.sub.2 CF.sub.2 H                                                     Convulsant                                                     CF.sub.3 CHCl-O-CF.sub.2 CHFCl                                                               Convulsant                                                     CF.sub.3 CH.sub.2 -O-CH.sub.2 CF.sub.3                                                       Convulsant                                                     CF.sub.3 CH.sub.2 -O-CF.sub.2 CH.sub.2 F                                                     Convulsant                                                     CF.sub.3 CH.sub.2 -O-CF.sub.2 CHFBr                                                          Anesthetic, convulsant                                                        properties.                                                    ______________________________________                                    

The effective amount of the compounds of this invention to be employeddepends on the level of anesthesia to which the mammal is to be brought,the rate at which anesthesia is to be induced, and the length of timeover which anesthesia is to be maintained. Minor volume percentages, forexample about 0.25 to 5%, or somewhat more, of the compounds inrespirable mixtures containing life-supporting amounts of oxygen can beemployed. The amount used should be sufficient to provide a significantanesthetic effect, but not so much as to produce unacceptabledeleterious side effects. The person controlling the anesthesia caneasily regulate the amount of the ether to be used, starting with asmall amount, e.g. about 0.25%, and gradually increasing the amountuntil the desired plane of anesthesia is reached. By then monitoring thephysical properties of the mammal, as is the usual procedure, theduration and plane of anesthesia can be readily controlled.

It should be understood that the foregoing disclosure relates topreferred embodiments of the invention and that it is intended to coverall changes and modifications of the examples of the invention hereinchosen for the purpose of the disclosure which does not constitutedeparture from the spirit and scope of the invention.

It is claimed:
 1. An inhalant anesthetic composition comprising CF₃ CHF--O--CF₂ --CHCl₂ and oxygen in suitable proportions for use as an anesthetic.
 2. The method of anesthetizing an anesthetic-susceptible mammal which comprises administering by inhalation to said mammal an anesthetically-effective amount of an ether compound of the formula

    CF.sub.3 CHF--O--CF.sub.2 CHCl.sub.2

as an inhalation anesthetic, while administering life-supporting amounts of oxygen. 